As the most common arrhythmia affecting ~2 million Americans, chronic atrial fibrillation (AF) is associated with numerous pathological sequelae such as stroke and tachycardia related cardiomyopathy. Therefore, optimizing treatment for AF is of paramount social and economical importance. Interventions to suppress the triggers for AF seem to be less effective than those that modify the substrate for AF. For example, some drugs that decrease the occurrence of premature beats are associated with increased mortality than placebos. Ablation of rapidly depolarizing foci from pulmonary veins, although a practical solution for many drug resistant AF cases, is largely limited by the high rate of AF recurrence. The curative rate of pulmonary vein isolation, which creates scar tissue around the pulmonary veins, is reported to be higher than ablation of triggering foci. Surgical MAZE procedures are curative in ~90% of selected cases, presumably because they provide a more complete substrate modification than does pulmonary vein isolation. The invasive nature and potential complications of these catheter or surgical procedures, however, continue to fuel the research for less invasive substrate modifying alternatives, such as gene therapy. Accordingly, this proposal seeks to develop a gene therapeutic modality for AF. We will test the hypothesis that overexpression of connexin 43 (Cx43) will increase conduction velocity through the atria in the absence of significant changes in tissue refractoriness, and that these changes will eliminate the substrate necessary to sustain fibrillation. To test this hypothesis, we will address 2 aims: (1)To exam the effects of overexpressed Cx43 on atrial conduction and refractory properties during sinus rhythm and preexisting AF; (2) To exam the effect of overexpressed Cx43 on the ability of the atria to sustain fibrillatory conduction in setting of underlying sinus rhythm or preexisting AF. Successful completion of these aims will allow us to determine the therapeutic potential of Cx43. The long term goal is to eventually translate experimental success into a cure for AF patients. [unreadable] [unreadable] [unreadable] [unreadable]